American Heart Association

Monthly Archives: July 2014

Toward a Simple MRI-Based Predictor of Successful Stroke Treatment

Mark N Rubin, MD
Yan S, Hu H, Shi Z, Zhang X, Zhang S, Liebeskind DS, and Min Lou M. Morphology of Susceptibility Vessel Sign Predicts Middle Cerebral Artery Recanalization After Intravenous Thrombolysis. Stroke. 2014

Although initial evaluation and management of stroke is typically straightforward, the dizzying array of “next steps” is matched in intensity only by the mountain of evidence that, in total, only equivocally supports any particular intervention beyond intravenous thrombolysis (IV tPA). We all just want our patients to get better, and it can be difficult if not impossible to make completely evidence-based management decisions in the timely fashion necessary for acute stroke.

All that said, stroke providers stand to benefit from the identification of biomarkers – ideally acquired during a standard clinical evaluation so as not to waste time – that inform prognosis and/or decision-making. Biomarkers of any sort would do, but there has been a focus on high-resolution neuroimaging with MRI in the hyperacute stroke setting in search of some such sign(s). This will surely continue in the era of 6-minute stroke MRI (not to be confused with the 7-minute workout), and MRI was the modality of choice for the investigators from China and the USA who contributed this biomarker study. They sought to clarify the controversy over the prognosticating value of the susceptibility vessel sign (SVS) in acute stroke.

The SVS in acute stroke, which seems to be the radiographic sign of an erythrocyte-rich or “red clot,” has been a tough nut to crack to this point. There have been conflicting studies through the years, with some showing the SVS is a predictor of recanalization and others suggesting the contrary. The SVS has all the makings of a simple, easily acquired and interpreted acute stroke biomarker, previous work suggests “red clots” are particularly amenable to tPA (at least in coronary arteries), and previous studies fail to definitively answer the question of the potential clinical use of the SVS, thus the interest in further research in this field. The investigators in this study performed a retrospective review of prospectively-collected MRI and clinical data from patients with MCA occlusions treated with tPA within 6 hours of symptom onset in order to determine potential prognostic value of the SVS.

The investigators were able to include 72 consecutive patients with acute stroke treated with IV tPA. The SVS was noted in 50/72 patients (~69%) and recanalization was only seen in 33 (~45%) patients at 24 hours. The mean clot length was ~14mm and shape irregularity was noted in 25/50 clots (50%). In brief, both SVS length and irregularity were independently associated with absence of recanalization at 24 hours. The cut-off length for prediction of recanalization was 14mm but no patients with a clot >20mm experienced recanalization.

This study suffers from a modest sample size and retrospective design, but represents the most “pure” sample of patients with SVS receiving tPA to date and an important step forward in our understanding of the SVS and its role as an acute stroke biomarker. Overall, the results suggest a long and/or irregular SVS predict absence of recanalization, something on the spectrum of “tPA failure.” There are many directions one can go with this information – and one should be cautious if considering any clinical decision-making based on these particular data – but the natural thought-leap, which the authors bring up in their discussion, is to best therapy for patients with an acute stroke and the SVS. Should a long and/or irregular clot prompt triage to the angiography suite post haste, with or without tPA, for endovascular reperfusion? Is an adjunctive antiplatelet infusion indicated in this setting? Might these be a subset of patients who benefit the most from sonothrombolysis? To parrot an oft-used phrase, further study is required. Let the hypothesis generation (and study design) begin!

Predicting Outcomes after Endovascular Therapy for Anterior Circulation Large Vessel Occlusions

Duy Le, MD

Rangaraju S, Liggins JTP, Aghaebrahim A, Streib C, Sun CH, Gupta R, et al. Pittsburgh Outcomes After Stroke Thrombectomy Score Predicts Outcomes After Endovascular Therapy for Anterior Circulation Large Vessel Occlusions. Stroke. 2014

While there have been multiple prior models which predict outcomes prior to thrombectomies as an effort to evaluate which patients are good thrombectomy candidates; Rangaraju et al have developed a prognosis model that carves out a unique niche. Rangaraju et al developed the The Pittsburg Outcomes after Stroke Thrombectomy (POST) Scale, which evaluates how patients will do after receiving a thrombectomy in hopes of providing information to families regarding prognosis to help guide patient management.

In this retrospective validation study, data was collected from a database at Grady Memorial Hospital (GMH) in Atlanta, Georgia. 247 patients were evaluated between 2009 and 2013. These patients met the criteria as follows: they were greater than 18 years of age and underwent endovascular therapy in the anterior circulation with large vessel occlusion (type of endovascular therapy was not specified) within 8 hours of last well known time. Baseline characteristics were measured, and after multivariant regression analysis, only age, final infarct volume and presence of hemorrhage (defined as presence of PH-1 or PH-2) were deemed to be independent predictors of good outcome. They then derived the following; POST Score = Age + 0.5xFIV + 15xH. A good outcome was defined as a modified rankin score of 0-2 at 3 months. 79% of GMH patients had successful recanalization (mTICI 2b/3). The POST score was deemed an excellent predictor of good outcome when evaluated on the GMH group (area under curve = 0.85). Scores that were <60 had a 91% chance of this good outcome, whereas a score of 60-89 carried a 59% chance of having a good outcome. A score of 90-119 had a 25% chance of a good outcome, while there was only a 4% chance of a good outcome with a score of greater than or equal to 120.  The POST score was then validated against two other registries; an institutional endovascular database (UPMC) and the DEFUSE-2 data set. Again, the score accurately predicted good outcomes in these registries as well. Additionally, the POST score was evaluated as a prediction model in those over 80 years of age and those who received the procedure later than 8 hours of last well known time. The general trend held true for these patients as well; a higher POST score was associated with a poorer outcome.

Some weaknesses of the study include the fact that the validating and derivative populations had significant baseline differencs. NIHSS, ASPECT score, IV-tPA, PH-1 and PH-2 rates as well as FIV were significantly different in the GMH, UMPC and DEFUSE-2 groups. UPMC patients had lower rates of IV-tPA (43.5% vs. 53% in the other two groups) and UPMC patients also had higher infarct volumes compared to the other two groups.  Additionally, 20% of patients in the derivation group and 8% in the validation group were excluded due to missing data points.

The goal of this score is to help guide the management of post thrombectomy patients, as many of these patients undergo gastrostomies or tracheostomies. Surrogate decision makers often base their decision to continue vs. withdraw care depending on the likelihood of a patient achieving functional independence.  While it is tempting to use the POST score as a surrogate marker in thrombectomy study patients to help dictate management; we must be careful in withdrawing care on these patients based on retrospective validation, as it may skew the results of the thrombectomy studies. To truly have a model that predicts outcome after thrombectomy, we will have to wait for a prospective validation study. And even then, we will have to await the results of this last wave of thrombectomy trials to see how applicable the POST score will ultimately be.

Hemodynamic quantification in brain arteriovenous malformations with time-resolved spin-labeled MRA

Daniel Korya, MD

Raoult H, Bannier E, Maurel P, Neyton C, Ferré JC, Schmitt P, et al. Hemodynamic Quantification in Brain Arteriovenous Malformations With Time-Resolved Spin-Labeled Magnetic Resonance Angiography. Stroke. 2014

Ruptured brain arteriovenous malformations (AVMs) represent about 2% of hemorrhagic strokes, but they can be quite devastating and often affect young people.  What if there was a way for us to predict which AVMs are more likely to rupture by quantifying some parameter?  That would be something.  Well, that is what Raoult and colleagues set out to do in this recent publication.

They used a 3T unenhanced time-resolved spin-labeled MRA (4D-SL-MRA) sequence of brain vessels to determine hemodynamic quantitative parameters in order to correlate them with progression of disease and rupture risk. 
In total, there were 16 patients in the study who were divided into groups based on AVM characteristics and prior rupture history.  One of the groups was considered to be the “High-Rupture-Risk” (HRR), while another was determined to be “Low-Rupture-Risk” (LRR).  Patients in the HRR were those with a history of ruptures (including asymptomatic bleeding signs on MRI), or exclusively deep venous drainage on DSA, or deep location.  There was another grouping that separated patients into hemorrhagic and non-hemorrhagic sub-groups. 
Essentially, what was observed was that patient’s in the HRR group (a majority of which had previous hemorrhages), were significantly more likely to have lower venous-to-arterial time-to-peak (TTP) ratio values.  The venous-to-arterial TTP ratio was below 2.0 in all cases that were more likely to rupture, and was thought to reflect higher velocities and exposure to higher vascular pressures within the AVM nidus.
Furthermore, by using the 4D-SL-MRA, the investigators argued that they were able to achieve temporal resolution in the range of 50-100 milliseconds, as compared with the usual 1-second times achieved by the current methods of contrast-enhanced MRA.  This provided for significantly better visualization of the vessels and limited vessel superposition. 
This modality allowed for accurate determination of the AVM’s main arterial feeders and draining veins as close to the nidus as possible, the nidus center, and the contralateral arteries corresponding to the main arterial feeders.  The level of detail obtained in a non-invasive way is certainly commendable and may be useful in not only predicting rupture risk, but also planning for treatment. 

Family History as a Risk Factor for Carotid Artery Stenosis

Rizwan Kalani, MD

Mahyar Khaleghi, Iyad N. Isseh, Hayan Jouni, Sunghwan Sohn, Kent R. Bailey, and Iftikhar J. Kullo. Family History as a Risk Factor for Carotid Artery Stenosis. Stroke. 2014

The impact of family history on ischemic stroke and its risk factors has been demonstrated. The risk conferred beyond that of traditional vascular risk factors, however, has been challenging to elucidate.

In this study, Khaleghi et al evaluated whether family history of stroke or coronary heart disease (CHD) was associated with carotid artery stenosis (CAS). They compared 864 patients with CAS (defined as 70% stenosis) and 1698 controls (who did not have CAS or atherosclerotic vascular disease history) that completed carotid artery doppler ultrasound over a six year period at a single institution. History of stroke/CHD in first-degree relatives before age 65 was obtained by questionnaire at the time of study recruitment. The principal finding was the prevalence of family history of stroke and CHD were significantly higher in patients with CAS compared with controls (stroke: OR 2.02; CHD: OR 2.01); sibling history of stroke/CHD was a stronger risk factor than parental history. The association was still significant after adjusting for age, sex and vascular risk factors (stroke: OR 1.41, CHD: OR 1.69). Having a greater number of affected relatives was associated with a higher odds of having CAS, independent of family size. Patients with the combination of 2 relatives with CHD and 2 relatives with stroke had an OR >7 compared to those who did not have this history.

This study demonstrates the role of family history of premature stroke/CHD in CAS risk. It suggests that there are likely genetic and environmental factors contributing to the development of CAS and that these are likely to be shared with CHD. Important limitations include the possibility of recall bias and predominant patient population being non-Hispanic Caucasian.
The authors note that future studies should address the utility of screening asymptomatic individuals for CAS who have a significant family history of vascular disease. I think that it also provides further evidence that the combination of next-generation sequencing methodologies and international collaborative efforts may identify novel genetic determinants of CAS. The potential to identify distinct pathophysiological mechanisms involved in CAS and allow for improved study of gene-environment interaction could pave the way for new stroke preventative and therapeutic options in the future.

Does the state you live in affect post-stroke discharge to rehab?

Ali Saad, MD

Skolarus LE, Burke JF, Morgenstern LB, Meurer WJ, Adelman EE, Kerber, et al. Impact of State Medicaid Coverage on Utilization of Inpatient  
Rehabilitation Facilities Among Patients With Stroke. Stroke. 2014

It may if you’re on Medicaid. This study suggests that residence plays an unfortunate role in a patient’s post stroke care. The authors examined 20,392 patients from the 2010 NIS (Nationwide Inpatient Sample) and followed whether they were discharged to IRFs (inpatient rehab facilities) versus other discharge destinations. All patients had Medicaid as their primary insurance and were of working age (18-64).

Of the 42 states analyzed, Medicaid did not cover IRFs in 4 states: TN, TX, SC, and WV. Having a stroke in one of these non-Medicaid IRF states conferred a 41% chance of not being discharged to an IRF compared to Medicaid-IRF states. No state-specific difference was found in non-Medicaid patients. It is especially concerning that this phenomenon is taking place in the “stroke belt”, which has a higher prevalence of stroke compared to the rest of the country.

The authors note that the accuracy of whether patients qualified for IRF is based on information from state-specific Medicaid websites. Nevertheless, a significant disparity remains. An important implication of this study is worsening health care disparity among working age minorities, although race/ethnicity was not available in the NIS database. Other factors including proximity of IRFs and patient preferences were not available in the NIS database.

Possible follow up studies include analyzing data from random hospitals in Medicaid-IRF versus non-Medicaid IRF states as the hospitals may have more patient demographic information than the NIS.

We have known for years that minority groups are at greater risk for the complications of stroke. Now stroke in the young is on the rise. Medicaid-IRF coverage requires further investigation to determine whether there is another target for improving health care disparities.

Does a cryptogenic stroke in a cancer patient spell doom?

Prachi Mehndiratta, MD

Navi BB, Singer S, Merkler AE, Cheng NT, Stone JB, Kamel HK, et al. Cryptogenic Subtype Predicts Reduced Survival Among Cancer Patients With Ischemic Stroke. Stroke. 2014

It is traumatic to experience a stroke and probably even more to not know what caused it. In about one-third of patients with acute ischemic stroke no clear etiology is found. It is hard to predict the recurrence risk of stroke in such patients particularly as the inciting factor or cause is not known. About 7% of patients with cancer experience a clinically significant stroke. These strokes can break their treatment cycles and often lead to significant disability. The authors in this article attempt to elucidate the frequency of cryptogenic stroke in patients with underlying malignancy as well as their outcomes after a cryptogenic stroke.

The authors identified 263 patients with acute ischemic stroke in a retrospective cohort of cancer patients admitted to their center between 2005 and 2009, by utilizing ICD 9 codes for stroke or transient ischemic attack. Patients that underwent only a CT scan and those seen exclusively in the outpatient setting were excluded due to concern for insufficient work up. Patients were followed till the primary outcome of death was reached or till July 31st 2012. Demographic, outcome and imaging data was rigorously collected and strokes were classified by using the TOAST classification. Stroke type was classified as cryptogenic if no clear cause was identified or if there were possibly two competing mechanisms. Multivariate cox proportional hazards analysis was used to determine an independent relationship between etiology of stroke and death and Kaplan-Meier survival curves were constructed.

Their results indicate that adenocarcinomas of solid organs such as lung, GI or GU tract were most often associated with ischemic stroke and stroke typically occurred about 10 months after cancer diagnosis. 69% of patients had disseminated disease at the time of stroke occurrence and stroke work up was equally comprehensive for the cryptogenic and non-cryptogenic stroke types. 133 of 263 patients were identified to have cryptogenic stroke and 76 of these had a cardioembolic appearing imaging pattern. Median survival among those with cryptogenic stroke was significantly lower (47 days vs. 141 days) as compared to those with known stroke mechanism and even lower in those that appeared cardioembolic (31 days). After adjusting for age, functional status, adenocarcinoma histology and known metastases, cryptogenic stroke type remained and independent predictor of death. (HR 1.64 95% CI (1.25-2.14)).

This study raised several important questions – does a cryptogenic stroke in a cancer patient spell doom? And if it does then what can we do to ascertain the cause better? One possible suggestion is that all patients undergo transesophageal echocardiogram and that the search for marantic endocarditis is more rigorous and a more comprehensive classification system such as the Causative Classification of Stroke (CCS) is employed to determine stroke etiology. I would have also liked to know a little more about differences in stroke severity between the two groups and if the patients underwent any repeat evaluations during follow up.  Practically speaking, should the patients that have a cryptogenic stroke and a cardioembolic appearing stroke be empirically treated with anticoagulation?

Change is not good: BP variability and ICH outcomes

Several studies have recently shown that even in the setting of better BP control, blood pressure variability may still have a negative effect on outcomes.  In this article, authors Tanaka et al utilized a prospective, multicenter, observational study to reinforce some of the previous findings.

205 patients were included, with inclusion criteria being age 20; initial SBP > 180, total GCS 5, supratentorial IPH and initial volume measurement < 60ml.  BP was measured every 15min for the first 2 hours after starting anti-HTN therapy, then every hour after that for the next 22 hours. Outcome measures included hematoma expansion, neurologic deterioration, and unfavorable outcomes of an MRS of 4-6 at 3 months.  On multivariate regression analyses, authors found standard deviation (SD) and successive variation (SV) of SBP to be associated with neurologic deterioration, and SV of SBP to be associated with unfavorable MRS outcomes at 3 months.  Neither SD or SV of SBP appeared to have significant associations with hematoma expansion.  There did not seem to be a significant link between SV/SD of DBP and any of the outcomes.

This study raises interesting questions about what the true causative agent is of the worse outcomes—is it a direct effect of variations in SBP, or are the negative effects somehow due to whatever caused that variation?  The authors touch on this, noting that “autonomic dysfunction, including sympathetic overactivity and diminished baroreflex sensitivity may be one of the mechanisms,” the thought being that these may contribute to altered perfusion, edema and secondary injury.   

This study, much like post-hoc analysis of INTERACT2, seems to imply that minimizing blood pressure variability in addition to aggressively lowering SBP may diminish rates of neurologic deterioration and improve long-term outcomes.  It will be interesting to see how this continues to play out in further studies, and if deterioration is found to be a direct effect of that variability or rather is just the effect of another, more damaging process.  If it is simply directly due to variability and we utilize effective methods to minimize that, what will we find “acceptable” levels of variability to be?

Brachial-ankle pulse wave velocity: A novel prognostic marker of recovery after stroke

Vivek Rai, MD

Kim J, Song TJ, Kim EH, Lee KJ, Lee HS, Nam CM, et al. Brachial-Ankle Pulse Wave Velocity for Predicting Functional Outcome in Acute Stroke. Stroke. 2014

The elastic component of arteries decreases with age and the consequent loss of elasticity results in hemodynamic changes, which are thought to be involved in pathogenesis of vascular diseases. Brachial-ankle pulse wave velocity (baPWV) is a recently developed automated tool for measurement of arterial elasticity used as an alternative to carotid-femoral pulse wave velocity (current gold standard). Carotid-femoral pulse wave velocity (cfPWV) and baPWV have been validated to produce reliable results and a high cfPWV is related to worse functional outcomes after stroke. The authors investigated whether baPWV can also be used as prognostic marker of recovery after stroke.

Kim et al analyzed data from1091 consecutive patients with first-ever acute cerebral infarction who underwent baPWV measurements. Poor functional outcomes were defined as modified Rankin Scale score of >2 at 3 months after stroke onset. The authors report that 181 (16.59%) patients had a poor functional outcome and the patients in the highest tertile of baPWV (>22.25 m/sec) were at an increased risk for poor functional outcome (adjusted OR, 1.88) compared to those in the lowest tertile (<17.55 m/sec). No significant interaction between baPWV and stroke subtype was noted.

The authors have shown that baPWV can be used as a simple, non-invasive marker for identification of patients at risk for poor recovery after stroke, regardless of stroke subtype according to TOAST criteria. In previous studies, increased baPWV and cfPWV were found to be independent predictors of new vascular events and cardiovascular mortality. It remains to be shown whether there is any causal effect to this association. Therapeutic interventions aimed at reducing progression of arterial stiffness may reduce stroke incidence and may even help in recovery after stroke. Further studies are necessary to prove these hypothesized benefits. Till then, in my view, the clinical application of this novel tool remains limited.

Can taped glasses and optokinetic training effectively treat neglect?

Matthew Edwardson, MD

Machner B, Könemund I, Sprenger A, von der Gablentz J, and Helmchen C. Randomized Controlled Trial on Hemifield Eye Patching and Optokinetic Stimulation in Acute Spatial Neglect. Stroke. 2014

Hemisensory neglect has a major detrimental impact on stroke recovery, impairing multiple activities of daily living. For this reason, many rehab experts feel that large right MCA strokes are worse than large left MCA strokes from a recovery stand point. Two strategies that demonstrate limited success in treating hemisensory neglect include hemifield eye patching (HEP) and optokinetic stimulation (OKS). HEP is somewhat akin to constraint-induced movement therapy of the limbs – the patient wears glasses that are taped with opaque tape over ½ of both lenses corresponding to the intact visual hemifield. OKS entails using an optokinetic strip to induce smooth pursuit eye movements, thereby correcting the shifted visuospatial midline experienced by these patients. In this article, Machner and colleagues compared a combined approach using HEP + OKS early after stroke to standard rehab in those with large right hemispheric strokes. They found that both groups achieved considerable improvement with no added benefit in the group receiving HEP + OKS.

The authors randomized 21 patients with right hemispheric stroke to one week of HEP + OKS within 14 days of stroke (n=11) vs. standard care (n=10). Study endpoints included a mean score from various tests for neglect, such as the Bell’s cancellation and line bisection tasks. Both the treatment and the control group demonstrated significant improvement on measures of neglect, both immediately after therapy and at one month. There was no significant difference between groups and notably no trends to suggest the study was underpowered.

The negative results of this study are frustrating but it may be premature to give up on HEP and OKS as therapeutic strategies for hemisensory neglect. The authors chose to test these interventions in the early phase after stroke. The rapid recovery that stroke patients achieve naturally during this phase may have washed out any difference between groups. In addition, testing endpoints beyond 30 days, which was not performed, may have shown separation between groups. The authors did an admirable job getting subjects to wear the taped glasses for all waking hours, yet I wonder if taped glasses are truly comparable to constraint-induced therapy of the limbs. For the glasses to be fully effective, the subject must look straight forward at all times. If the subject cheats by looking to the left or right, much of the effect would be lost. Perhaps a better intervention would entail contact lenses darkened on one side to maintain hemifield coverage regardless of the direction of gaze. Despite these minor concerns, this was a well-designed study of HEP + OKS to treat hemisensory neglect. The results suggest that more work is needed to identify an effective therapy for this debilitating condition.